From left: Prof. Michal Hershfinkel of Ben-Gurion University of the Negev, and Profs. Thanos Tzounopoulos and Elias Aizenman of the University of Pittsburgh, during a recent visit to Israel.

Sounds. They are so numerous and basic that it’s easy to take them for granted – unless something goes wrong.

While we know that sound gets processed in the brain, it’s still somewhat of a mystery how it gets processed. The findings of a current NSF-BSF-supported study could hold tremendous importance for understanding the very basic mechanisms of sound processing, sound adaptation (for example, diminished responses of the brain to constant or excessive sound stimulus), and hearing. This, in turn, will provide a solid basis for future studies that may help people with a variety of ailments affecting sound processing, such as hearing loss.

Profs. Michal Hershfinkel of Ben-Gurion University of the Negev, and Elias Aizenman of the University of Pittsburgh have been investigating the neurobiology of the metal zinc for years. Previously, with funding from two back-to-back regular BSF grants, their research has already yielded promising preliminary findings on how neurons use zinc as a signaling molecule. They are now joined by Prof. Thanos Tzounopoulos of the University of Pittsburgh, an expert on the auditory system. All three have now secured a major grant from the NSF-BSF partnership to help them continue the path to more discoveries.

When Hershfinkel and Aizenman began their joint study, they looked closely at the connections between neurons (the cells in the nervous system), zinc (contained within neurons), and synapses (which help neurons transfer interaction and communication between one another.) It is known that neurons contain zinc in their synaptic terminals, but the role of this zinc is not fully understood. Thanks to their findings so far, the team now has promising clues. Their findings revealed that zinc can be both an intracellular (inside neurons) and an extracellular (outside neurons) messenger.

“We have shown that sound exposure evokes zinc release from the synaptic vesicles. Once released, the zinc modulates sound processing. We show that zinc release inhibits the magnitude of response of auditory cortical neurons to sounds. We also showed that zinc enhances the ability of auditory cortical neurons to differentiate between sounds with different frequencies, which is a key feature of the auditory system. As a result, in the absence of zinc, mice were unable to detect the difference between frequencies that were narrowly spaced,” Tzounopoulos said.

Joint preliminary studies by the three investigators began to reveal clues on how zinc modulates sound processing and adaptation to sound. They determined that changes in the auditory environment rapidly modulate the levels of the proteins that regulate zinc levels (zinc transporters), suggesting a role of zinc in adaptive auditory processing.

With the help of the NSF-BSF partnership grant, the team is going further to analyze neuronal zinc and its effects on auditory processing.

The body processes sound, but the mechanisms of sound processing are still somewhat of a mystery. NSF-BSF investigators aim to find out more about them.

The team hopes to identify the pathways that are activated by sound-evoked zinc release, and understand how these pathways modulate sound processing. By understanding the basic roles of zinc in the synapses, the investigators may begin to understand how sound processing (discrimination between frequency or level of sound) is interpreted by the brain.

The investigators agree that the previous BSF grants, and the current NSF-BSF partnership grant, have helped them every step of the way.

“The previously-funded BSF projects allowed the establishment of a collaborative and synergistic experimental setup between our research groups,” Hershfinkel said. “These studies, which were based on the mutual interests of our laboratories, enabled us to interact and conceive novel hypotheses that were based on the distinct viewpoints and strengths of each of the principal investigators.”

Their research has already led to 11 joint papers published in leading scientific journals. Now, with the NSF-BSF grant, they can develop an even closer collaboration between themselves, their students, and their postdoctoral scholars.

“These grants have helped us work together in ways that have opened new avenues for our research. Moreover, we are delighted that the ongoing collaboration among the three laboratories has significantly enhanced the training opportunities of our students and postdocs,” Aizenman said. “We are making new discoveries, and at the same time, we are training the next generation who will make their own discoveries.”